Pulmonary arterial hypertension (PAH) is a life-threatening condition characterized by a progressive increase in pulmonary vascular resistance leading to right ventricular failure and death. Despite recent changes in treatment paradigms, there is no curative therapeutic options, and currently available therapies do not reverse pulmonary vascular remodeling and/or stop disease progression. To advance the management and improve outcomes of PAH patients, there is a significant need in new molecular targets for remodeling-focused therapeutic interventions. In established PAH, enhanced growth and survival of PA vascular smooth muscle (PAVSMC) and hyper-proliferation of endothelial cells (PAEC) both contribute to obliteration of the lumen of small PAs, pulmonary vascular remodeling and PAH. Thus, shared signaling molecules that selectively regulate hyper- proliferation of both, PAEC and PAVSMC, represent desirable targets for multi-cellular remodeling-focused therapeutic intervention. Our published and preliminary data strongly suggest that deficiency of transcription factor GATA6 is a shared pathological feature of PAEC and PAVSMC in human PAH and experimental PH, which is responsible for maintenance of hyper-proliferative cellular phenotypes, pulmonary vascular remodeling and pulmonary hypertension (PH). Specifically, we found that GATA6 is functionally connected via the bi- directional cross-talk to two key pathways regulating vascular homeostasis, growth-suppressing BMP10/BMPRII and pro-proliferative/pro-survival YAP, and supports expression and activity of several anti-oxidant enzymes including superoxide dismutase 2 (SOD2). Further, we demonstrate that endothelial-specific GATA6 deficiency promotes GATA6 loss and hyper-proliferation of PAVSMC and induces PA muscularization and spontaneous PH in mice. Lastly, we show that targeting GATA6 signaling reduces hyper-proliferation of human PAH pulmonary vascular cells and reverse PH in mice with EC-specific Gata6 deficiency. Based on published and new preliminary data, we hypothesize that GATA6 deficiency in distal PAEC and PAVSMC is required for maintenance of hyper-proliferative cellular phenotypes, remodeling of small PAs and overall PH. We also propose that GATA6 loss is supported by activation of Yap, BMPRII deficiency, and PAEC-PAVSMC communication, and, in turn, exacerbates pulmonary vascular remodeling by enabling Yap activation, BMPRII deficiency, and down-regulation of SOD2. Lastly, we propose that restoration of GATA6 signaling will selectively target hyper-proliferative PAEC and PAVSMC, reverse or attenuate pulmonary vascular remodeling and overall PH. To test our hypotheses, we will: (1) mechanistically investigate the role and functional significance of GATA6 deficiency in human PAH PAEC and PAVSMC; (2) determine the role of GATA6 loss in PAEC-PAVSMC interactions; (3) evaluate whether therapeutic targeting of GATA6 will reverse or attenuate pulmonary vascular remodeling and overall PH in preclinical rodent models of PH. The proposed study will identify new critical mechanisms and dissect new important molecular target for therapeutic intervention.